iPSC-Derived NK and Macrophage Combination Therapy
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Solution Overview
Problem
Current adoptive cell therapies for cancer, particularly CAR-T cell therapies, face challenges such as lengthy preparation times, donor variability in T cell quality, and adverse side effects like cytokine release syndrome, highlighting the need for standardized, "off-the-shelf" cell therapies with consistent quality and minimal side effects.
Innovation Solution
Administration of natural killer (NK) cells and macrophages, optionally combined with monoclonal antibodies targeting the CD47-SIRP pathway or other immune regulatory pathways, derived from induced pluripotent stem cells (iPSCs), to enhance cancer cell killing efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat cancer, then treatment efficacy is improved, but preparation time increases and side effects worsen
Solution Approach 1:
The patent applies preliminary action by using allogeneic NK cells that are pre-expanded and pre-activated ex vivo before administration. This allows the therapeutic cells to be prepared in advance from healthy donors, eliminating the need for time-consuming autologous T cell collection and expansion while maintaining treatment efficacy. The cells are ready for immediate infusion when needed.
Solution Approach 2:
The patent uses allogeneic NK cells from healthy donors as a standardized product that can be copied and manufactured consistently. Instead of relying on patient-specific T cells, the therapy uses donor-derived NK cells that can be expanded and prepared in advance, creating a reproducible off-the-shelf product that addresses both efficacy and preparation time concerns.
2Reliability
If autologous T cell therapy is used, then treatment efficacy is improved, but donor variability and manufacturing complexity worsen
Solution Approach 1:
The patent applies universality by using allogeneic NK cells from healthy donors that can be used for multiple patients. This standardized approach eliminates the need for individualized T cell manufacturing for each patient, reducing manufacturing complexity while maintaining treatment efficacy through the universal anti-tumor activity of NK cells.
Solution Approach 2:
The patent changes the source parameter from patient-specific T cells to donor-derived NK cells, and changes the activation state parameter by pre-activating the NK cells ex vivo. This allows for standardized manufacturing protocols with controlled expansion and activation conditions, reducing variability and simplifying the manufacturing process.
3Loss of time
If allogeneic NK cells are used, then preparation time is reduced, but anti-tumor efficacy worsens
Solution Approach 1:
The patent applies preliminary action by pre-expanding and pre-activating allogeneic NK cells ex vivo before administration. This preliminary preparation enhances the anti-tumor efficacy of the cells while maintaining the advantage of reduced preparation time compared to autologous T cell therapy, as the cells are ready for immediate infusion with optimized anti-tumor activity.
Solution Approach 2:
The patent changes the activation state parameter of the NK cells by treating them with specific activating conditions ex vivo, such as cytokine stimulation or engagement with activating antibodies. This parameter change enhances the anti-tumor efficacy of the allogeneic NK cells while maintaining the standardized, rapid preparation approach.
Data Source
AI summary
Compositions and combination cellular therapies with natural killer (NK) cells and macrophages for treating disease such a leukemia are disclosed herein. The compositions and therapeutic methods of administration may optionally include antibodies, such as anti-CD47 or other SIRP signaling inhibitors. The NK and macrophage cells may be produced from stem cells, and may optionally be produced from induced pluripotent stem cells (iPSCs), where the NK and macrophage cells may have enhanced antibody-dependent cellular cytotoxicity (ADCC). These immune cells may also be incorporated into pharmaceutical compositions. Methods for making the immune cells and pharmaceutical compositions, and methods of use thereof, are also provided.